PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3β pathway

Anita Palfi, Ambrus Toth, Katalin Hanto, Peter Deres, Eszter Szabados, Zoltan Szereday, Gyozo Kulcsar, Tamas Kalai, Kalman Hideg, Ferenc Gallyas, Balazs Sumegi, Kalman Toth, Robert Halmosi

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The inhibition of glycogen synthase kinase-3β (GSK-3β) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3β, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC α/βII, PKC δ and PKC ε, which could be responsible for the activation of the antihypertrophic GSK-3β. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3β intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.

Original languageEnglish
Pages (from-to)149-159
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume41
Issue number1
DOIs
Publication statusPublished - Jul 1 2006

Keywords

  • Glycogen synthase kinase-3β
  • Heart failure
  • Intracellular signaling
  • PARP inhibition
  • Protein kinase C
  • Ventricular remodeling

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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